scholarly journals What Is the Optimal Time to Initiate Hypomethylating Agents (HMA) in Higher Risk Myelodysplastic Syndromes (MDS)?

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3098-3098 ◽  
Author(s):  
Rami S. Komrokji ◽  
Najla Al Ali ◽  
David A Sallman ◽  
Eric Padron ◽  
Aziz Nazha ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Response Rate ◽  
Disease Risk ◽  
Response Rates ◽  
Complete Response ◽  
Optimal Time ◽  
Hypomethylating Agents ◽  
Advisory Committees ◽  
Baseline Characteristics

Abstract Background: Hypomethylating agents (HMA) are the standard of care for higher risk MDS patients (pts). Fewer than one-half will respond to therapy for an average duration of one year, thereby emphasizing the necessity to optimize the use of these disease modifying agents. HMA clinical trials have not addressed the optimal time in the disease course to initiate treatment to maximize disease-modifying potential. The current dogma is to begin HMA therapy in all higher risk MDS pts at the time of initial diagnosis. Nevertheless, a subset of higher risk MDS pts will have adequate hematopoiesis at the time of diagnosis regardless of disease risk, and for these pts therapy may be delayed and reserved for a later time when symptomatic cytopenias develop. We investigated the impact of the timing of HMA initiation on outcomes among higher risk MDS pts presenting with adequate blood counts to discern the possible benefit of early treatment based solely on disease risk. Methods: We identified MDS pts with intermediate-2 and high risk IPSS (higher risk) MDS treated with HMA among the Moffitt Cancer Center database. We included patients with adequate hematopoiesis defined for the purpose of this study as platelets >50 x 109/L, Hgb > 9 g/dl and ANC > 0.5 x 109/L and being transfusion independent to exclude those pts in need of HMA treatment for cytopenias. We divided patients into 4 groups based on the time of HMA initiation (within 30, 31-60 , 61-90 and greater than 90 days from time of diagnosis). We compared baseline characteristics, best response rate to treatment using international working group criteria (IWG 2006), leukemia free survival (LFS) and overall survival (OS) among the 4 groups. Results: We identified 320 higher risk MDS pts with adequate hematopoiesis who were treated with HMA. Baseline characteristics for the 4 groups based upon time of HMA therapy initiation are summarized in Table-1. Pts receiving treatment within 30 days had higher marrow myeloblast percentage at time of diagnosis. There was no difference in mean blood counts at time of diagnosis between the 4 groups; however, mean platelet count was lower at time of initiating HMA therapy in patients treated after 90 days from diagnosis. Table-2 summarizes somatic gene mutation data among 110 patients tested. TET-2 mutations were more common among those treated within 60 days, whereas U2AF1 mutations were more common among those treated after 60 days from diagnosis. The complete response rates were 21%, 26%, 23% and 7%, respectively for pts treated within 30 , 31-60 , 61-90 and greater than 90 days from time of diagnosis (p=0.046). The overall response rates (defined as hematological improvement or better) were 43%, 41%, 43% and 34%, respectively for pts treated within 30, 31-60 , 61-90 and greater than 90 days from date of diagnosis (p .70). There was no difference in mean duration of treatment with HMA among the groups with mean durations of 267, 204, 224 and 215 days, respectively, (p .35). The median OS from the date of diagnosis was 641, 550, 979 and 806 days, respectively for pts treated within 30, 31-60, 61-90 and greater than 90 days from date of diagnosis (p .2). There was no impact of timing for HMA initiation when adjusted for Revised-IPSS risk groups in Cox regression analysis. There was no difference in OS based on HMA initiation time when adjusted for myeloblasts % or karyotype. Further, there was no difference between groups in rate of AML transformation or LFS (p =.7 and .16, respectively). Conclusions A delay in initiating HMA therapy in higher risk MDS pts with adequate blood counts is not associated with worsened overall survival or increased frequency of leukemia transformation. Complete response rates were higher when treatment was started earlier in the disease course, however, there was no difference in overall response rate. Close observation to initiate treatment upon development of clinically significant cytopenias appears to be a safe and equally effective strategy among pts with higher risk MDS. Disclosures Komrokji: Novartis: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding. Sallman:Celgene: Research Funding, Speakers Bureau. Nazha:MEI: Consultancy. Steensma:Takeda: Consultancy; Syros: Research Funding; Otsuka: Membership on an entity's Board of Directors or advisory committees; Onconova: Consultancy; Novartis: Membership on an entity's Board of Directors or advisory committees; Kura: Research Funding; Janssen: Consultancy, Research Funding; H3 Biosciences: Research Funding; Celgene: Research Funding; Amphivena: Membership on an entity's Board of Directors or advisory committees; Acceleron: Consultancy. Roboz:AbbVie: Consultancy; Daiichi Sankyo: Consultancy; Jazz Pharmaceuticals: Consultancy; Cellectis: Research Funding; Novartis: Consultancy; Celltrion: Consultancy; Astex Pharmaceuticals: Consultancy; Sandoz: Consultancy; Celgene Corporation: Consultancy; Otsuka: Consultancy; Janssen Pharmaceuticals: Consultancy; Aphivena Therapeutics: Consultancy; Daiichi Sankyo: Consultancy; Orsenix: Consultancy; Bayer: Consultancy; Aphivena Therapeutics: Consultancy; Argenx: Consultancy; Orsenix: Consultancy; Novartis: Consultancy; Jazz Pharmaceuticals: Consultancy; Eisai: Consultancy; Celgene Corporation: Consultancy; AbbVie: Consultancy; Roche/Genentech: Consultancy; Cellectis: Research Funding; Otsuka: Consultancy; Bayer: Consultancy; Pfizer: Consultancy; Astex Pharmaceuticals: Consultancy; Argenx: Consultancy; Sandoz: Consultancy; Celltrion: Consultancy; Janssen Pharmaceuticals: Consultancy; Pfizer: Consultancy; Eisai: Consultancy; Roche/Genentech: Consultancy. Sekeres:Celgene: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Opsona: Membership on an entity's Board of Directors or advisory committees; Opsona: Membership on an entity's Board of Directors or advisory committees. List:Celgene: Research Funding.

scholarly journals A Phase 2 Trial of Ibrutinib and Nivolumab in Patients with Relapsed or Refractory Classical Hodgkin's Lymphoma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 29-29
Author(s):  
Walter Hanel ◽  
Beth A. Christian ◽  
Kami J. Maddocks ◽  
Narendranath Epperla ◽  
Basem M. William ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Median Time ◽  
Research Funding ◽  
Response Rate ◽  
Immune Escape ◽  
Chronic Gvhd ◽  
Complete Response ◽  
Median Number ◽  
Hodgkin's Lymphoma ◽  
Advisory Committees

Introduction: Classical Hodgkin's Lymphoma (cHL) is characterized by an extensive inflammatory infiltrate with abundant Th2 and Treg cells which facilitate immune escape of Reed Sternberg (RS) cells and provides a growth promoting microenvironment by cytokine secretion and CD40/CD40L engagement. Our group previously show that ibrutinib irreversibly inhibits both Bruton's tyrosine kinase (BTK) and interleukin-2 inducible kinase (ITK), a kinase important in Th2 signaling (Dubovsky et al Blood 2013). We hypothesized that the addition of ibrutinib to nivolumab would lead to deeper and more durable responses in cHL by normalizing the Th1/Th2 balance thus reversing immune escape of RS cells. We present results of a planned interim analysis of the first 10 patients enrolled with a data cutoff of June of 2020. Methods: This is a single arm, phase II, single institutional clinical trial testing the clinical activity of nivolumab in combination with ibrutinib in patients ≥18 years of age with histologically confirmed cHL who have received at least one prior line of therapy and who were either not candidates for or had a prior autologous stem cell transplant (ASCT). Prior treatment with nivolumab was allowed. Ibrutinib was administered at 560 mg daily until progression in combination with nivolumab 3 mg/kg IV every 3 weeks for 16 cycles. The primary objective was complete response rate (CRR) prior to cycle 7 assessed per Lugano criteria. Adverse events (AEs) were reported using CTCAE Version 4.0. Results: Of the first 11 cHL patients enrolled, one patient withdrew consent prior to initiating therapy. Of the remaining 10 patients, the median age was 41 years (range 20-84) and 4 patients (40%) were male. The median number of prior lines of treatment was 4.5 (range 1-11), 5 patients (50%) had prior ASCT, 8 patients (80%) had prior brentuximab, and 5 patients (50%) had prior nivolumab. Four of the five patients with prior nivolumab had progressed while receiving therapy while the remaining patient had stable disease upon completing nivolumab with a median time from the last nivolumab treatment of 15.6 months (range 0.7-23.2). Of the 10 patients who received treatment, one patient came off study after two cycles due to persistent grade 2 transaminitis lasting for several weeks attributed to nivolumab requiring high dose oral steroids. One patient came off study after cycle 9 due to grade 3 hematuria attributed to ibrutinib and another came off study due to a pericardial effusion after 8 cycles of ibrutinib maintenance. In the remaining patients, treatment was generally well tolerated with most AEs being grade 1-2 (Table 1). The median number of total cycles received was 9 (range 2-22). Of the 9 patients evaluable for response, 6 patients responded (ORR = 66%), 4 of whom had a complete response (CRR = 44%) with a median time to response of 2 months (Table 2, Fig.1). In intention-to-treat analysis, the ORR was 60% and CRR was 40% meeting our prespecified interim efficacy endpoint of a 30% CRR for trial continuation. Notably, of the 5 patients with prior nivolumab, 3 responded to nivolumab + ibrutinib (ORR = 60%), with one having a CR (CRR = 20%). Overall, at a median follow up of 9.5 months, both the median PFS and duration of response have not yet been reached, with 3 patients remaining in CR at the time of data cutoff. Three of 4 patients discontinued trial treatment to undergo SCT [2 allogeneic; 1 autologous]. Of the 2 allogeneic SCT patients, the first one underwent SCT 3 weeks after the last nivolumab infusion and developed multi-organ acute graft-versus-host disease (GVHD) followed by severe chronic GVHD requiring extracorporeal photopheresis. The second patient underwent allogeneic SCT 2 months following the last nivolumab infusion and had no acute GVHD and experienced only mild chronic GVHD which was medically managed. Conclusions: Although the numbers are small and further recruitment is ongoing (target n=17), the combination of ibrutinib and nivolumab was generally well tolerated and with high response rate with more than half of responding patients achieving a CR. In addition, responses were seen in patients with prior nivolumab treatment. Our results suggest a possible novel role for BTK inhibition in reversing nivolumab resistance in cHL, at least in some cases. Correlative studies including peripheral blood and tumor immune subset analyses are ongoing and the latest results will be presented at the meeting. Disclosures Christian: Acerta: Research Funding; Celgene: Research Funding; Genentech: Research Funding; Merck: Research Funding; Millenium: Research Funding; MorphoSys: Research Funding; F Hoffman-La Roche: Research Funding; Triphase: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Verastem: Membership on an entity's Board of Directors or advisory committees; AstraZenica: Membership on an entity's Board of Directors or advisory committees. Maddocks:Morphosys: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Karyopharm: Consultancy; ADC Therapeutics, AstraZeneca: Consultancy; BMS: Consultancy, Research Funding; Pharmacyclics: Consultancy, Honoraria. Epperla:Verastem Oncology: Speakers Bureau; Pharmacyclics: Honoraria. William:Incyte: Research Funding; Dova: Research Funding; Celgene: Consultancy, Honoraria; Seattle Genetics: Research Funding; Merck: Research Funding; Kyowa Kirin: Consultancy, Honoraria; Guidepoint Global: Consultancy. Jaglowski:Novartis: Consultancy, Research Funding; CRISPR: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; Juno: Consultancy. Bond:Seattle Genetics: Honoraria. Brammer:Celgene Corporation: Research Funding; Seattle Genetics, Inc.: Speakers Bureau. Baiocchi:viracta: Consultancy, Membership on an entity's Board of Directors or advisory committees; Prelude Therapeutics: Consultancy, Research Funding. OffLabel Disclosure: This trial uses ibrutnib in cHL to augment the responses of concurrent nivolumab administration.

Long-Term Outcome Following B-Cell Depletion Therapy with Rituximab In Children and Adults with Immune Thrombocytopenia (ITP)

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 72-72 ◽  
Author(s):  
Vivek L. Patel ◽  
Matthieu Mahévas ◽  
Roberto Stasi ◽  
Susanna Cunningham-Rundles ◽  
Bertrand Godeau ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Response Rate ◽  
Initial Response ◽  
Response Rates ◽  
Advisory Committees ◽  
Term Outcome ◽  
Long Term Outcome ◽  
One Year

Abstract Abstract 72 Background: Studies of B-cell depletion using Rituximab in adults with ITP report responses lasting at least one year in almost all of the 30–40% of patients with complete responses (CR: platelet count >150 × 109/l) and also a small fraction of patients with partial responses (PR: platelet count 50–150 × 109/l). However data describing patients with ITP who are relapse-free and off-treatment beyond 1–2 years from initial Rituximab are almost entirely anecdotal and comparable response data are even less available for children. This study assessed the duration of unmaintained platelet response following rituximab treatment in 72 adults and 66 children with ITP, all of whom had had at least an initial response to rituximab. Long-term outcome was estimated from these data. Methods: Seventeen published studies including 486 patients, 376 adults and 110 children, were used to obtain the initial response rates to standard-dose rituximab treatment (375mg/m2 weekly for 4 weeks) in adults and children. Only 1 included study did not use the standard dose of rituximab. The Godeau study (Blood, 2008) was used to estimate the one-year response rate in adults with ITP. Only those adults whose responses persisted at least one year had follow up assessed whereas children who demonstrated even ephemeral responses were included. Only verified counts were used in this IRB-approved multicenter study. Results: 138 subjects with CR's or PR's after rituximab were included. All patients had starting platelet counts <30×109/l and 131 (95%) had ITP of > 6 months duration. Thirty-three (24%) had undergone splenectomy. Using the data from prior publications to obtain the initial response rates, children had a 56% initial response rate to rituximab treatment and adults had a 57% rate. Taking initial responders and then using the Godeau data for adults and Kaplan-Meier analysis of our data for children, 38% one-year response rates were obtained for both children and adults treated with rituximab. Both age groups also showed remarkable similarity at two years with 30% relapse-free response rates. However, all of the 26 eligible children maintained their response beyond two years whereas adults continued to relapse. Therefore the five-year response rate was 30% for children and only 21% for adults. Sex, duration of ITP, and age among adults did not affect long-term outcome. The rate of relapse was almost identical for splenectomized patients and non-splenectomized ones but the splenectomized patients appeared to relapse sooner (Figure). Patients with CR's (55 of the 72 adults with responses lasting at least one year were CR's) had better long-term outcomes than did patients with PR's even more than one year from initial treatment. B-cells returned significantly sooner to higher levels in subjects who relapsed compared to those whose responses were ongoing. No clinical long-term toxicity was observed but 2 patients were identified to have mild hypogammaglobulinemia > 30 months from initial treatment. Conclusions: In summary, only approximately 1 in 5 adults treated with rituximab will have an at least five-year relapse-free response rate which is disappointingly low; children have only a slightly higher five-year relapse-free response rate. A pilot study to improve outcomes using either R-CVP or double dose rituximab was unsuccessful (Hasan, Am J Hematol,2009) Current efforts to improve long-term response rates have focused on the combination of high dose dexamethasone and rituximab (or even by providing maintenance treatment with rituximab). A better understanding of the mechanism of effect of rituximab in patients with ITP might allow an improved treatment strategy to be developed. Fortunately, the toxicity of rituximab treatment in patients with uncomplicated ITP appears to be low; however, yearly testing for immunoglobulins for a minimum of five years might be appropriate. Disclosures: Neufeld: Novartis. Inc: Research Funding. Shenoy:Novartis Oncology: Honoraria. Bussel:Amgen: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cangene: Research Funding; GlaxoSmithKline: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genzyme: Research Funding; Immunomedics: Research Funding; Ligand: Membership on an entity's Board of Directors or advisory committees, Research Funding; Eisai Inc: Membership on an entity's Board of Directors or advisory committees, Research Funding; Shionogi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sysmex: Membership on an entity's Board of Directors or advisory committees, Research Funding; Portola: Consultancy.

scholarly journals Machine Learning Prediction for Complete Response to Hypomethylating Agents with or without Additional Agents in Patients with Newly Diagnosed Myelodysplastic Syndrome

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1720-1720
Author(s):  
Koji Sasaki ◽  
Guillermo Montalban Bravo ◽  
Rashmi Kanagal-Shamanna ◽  
Elias Jabbour ◽  
Farhad Ravandi ◽  
...  
Keyword(s):  
Machine Learning ◽  
Board Of Directors ◽  
Research Funding ◽  
Area Under The Curve ◽  
Complete Response ◽  
Learning Model ◽  
Hypomethylating Agents ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Machine Learning Model

Background: Myelodysplastic syndrome (MDS) is a heterogeneous malignant myeloid neoplasm of hematopoietic stem cells due to cytogenetic alterations and somatic mutations in genes (DNA methylation, DNA repair, chromatin regulation, RNA splicing, transcription regulation, and signal transduction). Hypomethylating agents (HMA) are the standard of care for MDS, and 40-60% of patients achieved response to HMA. However, the prediction for response is difficult due to the nature of heterogeneity and the context of clinical conditions such as the degree of cytopenias and the dependency on transfusion. Machine learning outperforms conventional statistical models for prediction in statistical competitions. Prediction with machine learning models may predict response in patients with MDS. The aim of this study is to develop a machine learning model for the prediction of complete response (CR) to HMA with or without additional therapeutic agents in patients with newly diagnosed MDS. Methods: From November 2012 to August 2017, we analyzed 435 patients with newly diagnosed MDS who received frontline therapy as follows; azacitidine (AZA) (3-day, 5-day, or 7-day) ± vorinostat ± ipilimumab ± nivolumab; decitabine (DAC) (3-day or 5-day) ± vorinostat; 5-day guadecitabine. Clinical variables, cytogenetic abnormalities, and the presence of genetic mutations by next generation sequencing (NGS) were included for variable selection. The whole cohort was randomly divided into training/validation and test cohorts at an 8:2 ratio. The training/validation cohort was used for 4-fold cross validation. Hyperparameter optimization was performed with Stampede2, which was ranked as the 15th fastest supercomputer at Texas Advanced Computing Center in June 2018. A gradient boosting decision tree-based framework with the LightGBM Python module was used after hyperparameter tuning for the development of the machine learning model with training/validation cohorts. The performance of prediction was assessed with an independent test dataset with the area under the curve. Results: We identified 435 patients with newly diagnosed MDS who enrolled on clinical trials as follows: 33 patients, 5-day AZA; 23, 5-day AZA + vorinostat; 43, 3-day AZA; 20, 5-day AZA + ipilimumab; 19 patients, AZA + nivolumab; 7, AZA + ipilumumab + nivolumab; 114, 5-day DAC; 74, 3-day DAC; 4, DAC + vorinostat; 97, 5-day guadecitabine. In the whole cohort, the median age at diagnosis was 68 years (range, 13.0-90.3); 117 (27%) patients had a history of prior radiation or cytotoxic chemotherapy; the median white blood cell count was 2.9 (×109/L) (range, 0.5-102); median absolute neutrophil count, 1.1 (×109/L) (range, 0.0-55.1); median hemoglobin count, 9.5 (g/dL) (range, 4.7-15.4); median platelet count, 63 (×109/L) (range, 2-881); and median blasts in bone marrow, 8% (range, 0-20). Among 411 evaluable patients for the revised international prognostic scoring system, 15 (4%) had very low risk disease; 42 (10%), low risk; 68 (17%), intermediate risk; 124 (30%), high risk; and 162 (39%), very high risk. Overall, 153 patients (53%) achieved CR. Hyperparameter tuning identified the optimal hyperparameters with colsample by tree of 0.175, learning rate of 0.262, the maximal depth of 2, minimal data in leaf of 29, number of leaves of 11, alpha regularization of 0.010, lambda regularization of 2.085, and subsample of 0.639. On the test cohort with 87 patients, the machine learning model accurately predicted response in 65 patients (75%); 53 non-CR among 56 non-CR (95% accuracy); and 12 CR among 31 CR (39% accuracy). The trend of accuracy improvement by iteration (i.e., the number of decision trees) is shown in Figure 1. The area under the curve was 0.761521 in the test cohort. Conclusion: Our machine learning model with clinical, cytogenetic, and NGS data can predict CR to HMA in patients with newly diagnosed MDS. This approach can identify patients who may benefit from HMA therapy with and without additional agents for response, and can optimize the timing of allogeneic stem cell transplant. Disclosures Sasaki: Otsuka: Honoraria; Pfizer: Consultancy. Jabbour:Takeda: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Cyclacel LTD: Research Funding. Ravandi:Cyclacel LTD: Research Funding; Selvita: Research Funding; Menarini Ricerche: Research Funding; Macrogenix: Consultancy, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Xencor: Consultancy, Research Funding. Kadia:Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Bioline RX: Research Funding; Jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Research Funding; BMS: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Takahashi:Symbio Pharmaceuticals: Consultancy. DiNardo:syros: Honoraria; jazz: Honoraria; agios: Consultancy, Honoraria; celgene: Consultancy, Honoraria; notable labs: Membership on an entity's Board of Directors or advisory committees; medimmune: Honoraria; abbvie: Consultancy, Honoraria; daiichi sankyo: Honoraria. Cortes:Novartis: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Immunogen: Consultancy, Honoraria, Research Funding; Sun Pharma: Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Astellas Pharma: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Merus: Consultancy, Honoraria, Research Funding; Forma Therapeutics: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; BiolineRx: Consultancy; Biopath Holdings: Consultancy, Honoraria; Takeda: Consultancy, Research Funding. Kantarjian:AbbVie: Honoraria, Research Funding; Cyclacel: Research Funding; Pfizer: Honoraria, Research Funding; Astex: Research Funding; Agios: Honoraria, Research Funding; Jazz Pharma: Research Funding; Daiichi-Sankyo: Research Funding; Novartis: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Immunogen: Research Funding; Takeda: Honoraria; BMS: Research Funding; Ariad: Research Funding; Amgen: Honoraria, Research Funding. Garcia-Manero:Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding.

scholarly journals Efficacy and Safety of Single-Agent Ibrutinib in Patients with Mantle Cell Lymphoma Who Progressed after Bortezomib Therapy

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4471-4471 ◽  
Author(s):  
Michael Wang ◽  
Andre Goy ◽  
Peter Martin ◽  
Rod Ramchandren ◽  
Julia Alexeeva ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Response Rate ◽  
Single Agent ◽  
Complete Response ◽  
Employment Equity ◽  
Advisory Committees ◽  
Bulky Disease ◽  
Equity Ownership ◽  
Grade 3

Abstract Introduction: Despite recent advances, mantle cell lymphoma (MCL) remains difficult to treat with frequent chemoresistance in the relapsed or refractory setting. Ibrutinib, a first-in-class, once-daily, oral covalent inhibitor of Bruton’s tyrosine kinase, demonstrated durable single-agent efficacy in a previous phase 2 study of patients with MCL who had received 1 to 5 prior therapies (Wang M, et al. N Engl J Med. 2013;369:507-516). In that study, the investigator-assessed overall response rate was 68% (complete response rate, 21%). The current study reports on the efficacy and safety of single-agent ibrutinib specifically in patients with MCL who had received a rituximab-containing regimen and had progressed after at least 2 cycles of bortezomib therapy. Methods: In this phase 2, multicenter, single-arm study, patients received 560 mg/day oral ibrutinib continuously until progressive disease or unacceptable toxicity. The primary end point was the overall response rate (ORR) in response evaluable patients, as assessed by an Independent Review Committee (IRC). Secondary end points, also assessed by IRC, included duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety. Results: 120 patients in this international multicenter study were enrolled. The median age was 67.5 years, ranging from 35 to 85 years with 62.5% ≥ 65 years. Most patients had stage IV disease at study entry (77.5%), and 9.2% were reported as blastoid variant (per investigator). 76.3% of patients had an intermediate or high risk simplified MIPI score, and 52.5% had bulky disease (longest diameter ≥ 5 cm). Forty two (35.0%), 67 (55.8%) and 11 patients (9.2%) had an ECOG score of 0, 1 and 2, respectively. The median number of prior lines of systemic therapy was 2 (range 1-8 lines) with almost half of the patients (47.5%) receiving 3 or more prior lines of therapy. Overall, 33% of patients had received prior stem cell transplantation. At the time of clinical cut-off for the primary analysis (29 April, 2014), median follow-up was 14.9 months with median treatment duration of 8 months (range: 0.5-20.9 months). The main reasons for treatment discontinuation were disease progression in 53 patients (44.2%) and an adverse event (AE) in 8 patients (6.7%). The ORR for response evaluable patients was 62.7% (95% confidence interval [CI]: 53.7%-71.8%) with a complete response rate of 20.9%. Subgroup analysis suggested that the ORR was independent of age, gender, geographic region, number of prior lines of therapies, baseline extranodal disease, simplified MIPI score, bulky disease, and stage of MCL. Median DoR by IRC was 14.9 months and the median time to first response was 2.1 months, ranging from 1.3 to 6.3 months. Median PFS was 10.5 months and 47% of the patients remained progression-free at 1 year. The OS rate at 18 months was 61%. The most common AEs were fatigue (any grade, 43.3%; grade 3 or 4, 3.3%) and diarrhea (any grade, 42.5%; grade 3 or 4, 2.5%). The most common grade 3 or higher AEs were neutropenia (20.8%), thrombocytopenia (13.3%), and pneumonia (12.5%). Any-grade hemorrhagic events were reported in 45 patients (37.5%), including 3 (2.5%) with major hemorrhagic events. The median time to initial hemorrhagic event was 84 days (range 1-515 days), with a median duration of 22 days (95% CI: 8-31 days). Atrial fibrillation was reported in 13 patients (10.8%), which was grade 3 or 4 in 6 patients (5%). AEs led to dose reductions in 8 patients (6.7%). Conclusion: Single agent ibrutinib is highly efficacious and well tolerated, with an acceptable toxicity profile in patients with MCL who progressed after rituximab-containing chemotherapy and bortezomib therapy. These results are consistent with previous ibrutinib studies, with no new safety signals. Disclosures Wang: Pharmacyclics, Janssen, Celgene, Onyx, OnyPep, : Research Funding; Onyx, Janssen: Honoraria. Goy:Janssen/Pharmacyclics: Honoraria, Speakers Bureau; Clinical Trials through Institution: Research Funding; Janssen/Pharmacyclics: Membership on an entity's Board of Directors or advisory committees. Martin:Janssen: Honoraria. Popat:Janssen: Honoraria. Advani:Seattle Genetics, Genetech, (Uncompensated): Membership on an entity's Board of Directors or advisory committees; Janssen, Pharmacyclics, Seattle Genetics: Research Funding. Le Gouill:Roche: Consultancy; Janssen: Consultancy. Yuan:Johnson & Johnson: Equity Ownership; Johnson & Johnson: Employment. Kranenburg:Johnson&Johnson: Equity Ownership; Janssen Biologics: Employment. Rizo:Janssen R&D: Employment, Equity Ownership. Zhuang:Johnson & Johnson: Employment, Equity Ownership. Deraedt:Johnson & Johnson: Employment, Equity Ownership. Rule:Pharmacyclics, J&J: Consultancy, Membership on an entity's Board of Directors or advisory committees.

scholarly journals A Phase Ib/II Study of Ibrutinib in Combination with Obinutuzumab-Gazyva As First-Line Treatment for Patients with Chronic Lymphocytic Leukemia > 65 Years Old or with Coexisting Conditions

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1863-1863
Author(s):  
Juliana Velez Lujan ◽  
Michael Y. Choi ◽  
Chaja Jacobs ◽  
Colin McCarthy ◽  
Alaina Heinen ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Overall Response Rate ◽  
Response Rate ◽  
Single Agent ◽  
Complete Response ◽  
Lymphocytic Leukemia ◽  
Advisory Committees ◽  
Grade 3

Abstract Standard treatment for patients with chronic lymphocytic leukemia (CLL) is rapidly evolving and gradually has incorporated the combined use of monoclonal antibodies (mAbs) and targeted therapy with small molecules. Single agent Ibrutinib (Ibr), a first-in-class BTK inhibitor, is effective in previously untreated patients including those that are older than 65 or considered unfit to receive chemotherapy-based combinations. The complete response rate in patients receiving single agent Ibr is relatively low (overall response rate of 86% and complete response of 4% based on 2008 iwCLL criteria), though most patients have durable remissions. The combination of Ibr with mAbs like Obinutuzumab-Gazyva (G), a third-generation anti-CD20 mAb, can ameliorate the Ibr-induced lymphocytosis and increase the overall and complete response rates. Accordingly, we initiated an open-label phase Ib/II clinical study of Ibr in combination with G for first-line therapy of previous untreated pts with CLL. The study completed enrollment of 32 previously untreated patients with CLL. Patients received G administered based on FDA dosing recommendations for 6 cycles (28 days/cycle) and Ibr 420mg po (1-3 hours before starting G infusion), and daily for up to 3 years. All patients received prophylactic medications. Patients were assessed for response by 2008 iwCLL criteria two months after completion of G, as the primary efficacy endpoint. The median age of the patients was 65 (range: 46-78) years. 84% of the patients had a CIRS >6, 45% had a Rai stage III-IV and 19% had an ECOG performance ≤2. The median baseline absolute lymphocyte count (ALC) was 79x103/mm3(range: 1.4-412.4). Patients showed the following FISH/cytogenetic abnormalities: del(13q) in 55%, trisomy 12 in 23% and del(11q) in 19%. Only 2 (6%) of these patients showed del(17p). From the patients with IGVH mutational status available (n=17), 11 (65%) were unmutated (>98% homology). Most adverse events (AEs) were grade 1-2 (74%). Six patients (19%) had grade 1-2 G-infusion-related reaction (IRR) and only one patient (3%) showed grade 3 IRR (without the need for G discontinuation). We observed neutropenia (all grades: 52%, grade 3-4: 23%), thrombocytopenia (all grades: 71%, grade 3-4: 19%) and anemia (all grades: 26%). There were no cases of febrile neutropenia. Two patients (6%) had grade 1 bleeding (one patient with asymptomatic lower gastrointestinal bleeding and the second patient with epistaxis) that resolved spontaneously without requirement of blood transfusion or study treatment discontinuation. Two patients (6%) developed pneumonia, one was community-acquired pneumonia requiring inpatient treatment with IV antibiotics; the study treatment was held until resolution of symptoms and re-initiated at full dose. The most frequent non-hematological AEs were diarrhea, transaminitis, hyperbilirubinemia, hyperglycemia, and electrolyte alterations (grade 1-2). Three patients (9%) discontinued Ibr due to atrial fibrillation grade 1 (n=1), rash and headaches grade 2 (n=1), and persistent grade 4 thrombocytopenia (n=1). Twenty-three patients were evaluable for response assessment by 2008 iwCLL criteria (median follow-up of 11 months). 84% of the patients showed a rapid decrease in ALC from baseline during the first cycle of treatment and only four patients (13%) required more than 3 cycles of treatment to achieve an ALC response. The overall response rate was 100%. The majority of pts had a partial response and six of 23 evaluable patients (26%) achieved a complete remission with detectable Minimal Residual Disease in the bone marrow by multiparametric flow cytometry. In summary, Ibr-G combination has been generally well tolerated. AEs have been consistent with the known safety profiles of Ibr and G individually. The patients that discontinued Ibr remain in follow-up without disease progression. 100% of evaluable patients achieved response after 6 months of combination therapy, and 26% of patients met CR criteria. One important finding thus far has been a very low rate of IRR, (19% grade 1-2 and 3% grade 3-4), suggesting that Ibr can strongly mitigate the incidence and severity of G associated IRR. Disclosures Choi: AbbVie, Inc: Consultancy, Speakers Bureau; Rigel: Consultancy; Gilead: Speakers Bureau; Pharmacyclics: Consultancy, Research Funding, Speakers Bureau; Genentech: Speakers Bureau. Amaya-Chanaga:AbbVie: Equity Ownership, Other: Research performed while employed as an investigator of this study at UCSD. Review and approval of abstract performed while employed at Pharmacyclics, LLC, an AbbVie Company.; Pharmacyclics, an AbbVie Company: Employment, Other: Research performed while employed as an investigator of this study at UCSD. Review and approval of abstract performed while employed at Pharmacyclics, LLC, an AbbVie Company.. Kipps:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; Celgene: Consultancy; Verastem: Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Research Funding; Genentech Inc: Consultancy, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: Membership on an entity's Board of Directors or advisory committees. Castro:F. Hoffmann-La Roche: Consultancy; Genentech, Inc: Consultancy; Pharmacyclics, LLC, an AbbVie Company:: Consultancy.

scholarly journals Anti-CD123 Targeted Therapy with Talacotuzumab in Advanced MDS and AML after Failing Hypomethylating Agents - Final Results of the Samba Trial

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4045-4045 ◽  
Author(s):  
Anne Sophie Kubasch ◽  
Freya Schulze ◽  
Katharina S. Götze ◽  
Jan Krönke ◽  
Katja Sockel ◽  
...  
Keyword(s):  
Nk Cells ◽  
Board Of Directors ◽  
Research Funding ◽  
Treatment Initiation ◽  
Response Rate ◽  
Nk Cell ◽  
Single Agent ◽  
Hypomethylating Agents ◽  
Advisory Committees ◽  
Disease Stabilization

Abstract Introduction Recently, progress has been made in the treatment of patients with higher risk myelodysplastic syndromes (HR MDS) and acute myeloid leukemia (AML). Nevertheless, patients failing hypomethylating agents (HMA) have a dismal prognosis and very limited treatment options. Targeting CD123 on leukemic stem cells (LSC) is one promising approach in MDS and AML. Talacotuzumab (TAL, JNJ-56022473) is an IgG1 monoclonal antibody targeting CD123 preferentially via antibody-dependent cellular cytotoxicity (ADCC) mediated by natural killer cells (NKs). Aim The SAMBA trial, a phase II study of the German and French MDS study groups within the EMSCO network assessed the overall hematological response rate after 3 months of single agent TAL treatment in AML or HR MDS patients failing hypomethylating agents (HMAs). Methods TAL was given IV at a dose of 9 mg/kg once every two weeks for a total of 6 infusions, responders received up to 20 additional infusions. After the first 3 months, overall hematological response rate (either CR, PR, marrow-CR, HI, SD) was evaluated by bone marrow biopsy. The study was accompanied by an immune monitoring via flow cytometric analysis to investigate the distribution of T- and NK cells in peripheral blood (PB) and bone marrow (BM) at the time of screening and during therapy in comparison with healthy, age-matched controls. Results 24 patients (19 AML and 5 HR MDS) with a median age of 77 (range 71-90) years, who either failed to achieve complete- (CR), partial response (PR), hematological improvement (HI) or relapsed after HMA therapy were included in the study. After TAL administration, 14 patients could be assessed for response after 4 infusions and 10 patients after 6 infusions. The overall response rate (ORR) was 20.8% including 1 complete remission (CRi), 1 patient with hematologic improvement (HI-E) and additionally 3 patients with disease stabilization. The median duration of response in these patients was 3 months (range 3-14 months). Two patients are still on treatment, one patient despite losing objective response (14 months) and one patient with disease stabilization (13 months). The median overall survival for the entire cohort of patients was 3.2 months (range 0.4-11.2 months). In 10 patients (41.6%), therapy with TAL resulted in grade 3/4 infusion related side effects (pneumonia, n=1; infusion-related reaction, n=8; septic shock, n=1). Before treatment initiation, patients had lower levels of CD56dim NK-cells in PB (82% vs. 89% of NK-cells; p=0.069) expressing significantly more inhibiting NK-cell receptors like KIR2DL2 (8.8% vs. 3.2% of NK-cells; p<0.001) and less activating NK-cells receptors like NKG2D (95% vs. 99% of NK-cells; p<0.01) compared to healthy controls. Moreover, expression of PD-1 on lymphocytes and monocytes as well as their matching ligands PD-L1 and PD-L2 on blasts and monocytes in PB was significantly higher in patients compared to healthy controls (p<0.01), another evidence for an exhausted T-cell immune status in our patients prior to treatment initiation. We could not detect any difference in NK-cell levels in responding patients compared to non-responders. Interestingly, pre-treatment expression (MFI and percentage) of CD123 on immature myeloid derived suppressor cells (iMDSC) was higher in responders than in non-responders (p<0.01). Anti-CD123 targeted therapy with TAL resulted in a decreased CD123+ MFI (4239 vs. 2910; p<0.01) on iMDSCs as well as lower levels of iMDSCs in PB and BM (p<0.05).Responding patients displayed a 10-fold reduction of CD123 MFI after 3 months of treatment (2565 vs. 236; p=0.06), indicating that the CD123 molecule on immature MDSCs is targeted effectively by TAL. Conclusion Single agent TAL has limited efficacy in patients with advanced myeloid malignancies failing HMA. Expression of CD123 on immature MDSCs might serve as a biomarker of response for future anti-CD123 targeted approaches. Disclosures Götze: Celgene: Honoraria, Research Funding; JAZZ Pharmaceuticals: Honoraria; Novartis: Honoraria; Takeda: Honoraria, Other: Travel aid ASH 2017. Krönke:Celgene: Honoraria. Middeke:Roche: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Fenaux:Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Otsuka: Honoraria, Research Funding. Schlenk:Pfizer: Research Funding, Speakers Bureau. Ades:JAZZ: Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees; silent pharma: Consultancy; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Platzbecker:Celgene: Research Funding.

scholarly journals Depth of Response and Response Kinetics in the Icaria-MM Study of Isatuximab with Pomalidomide/Dexamethasone in Relapsed/Refractory Multiple Myeloma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3185-3185 ◽  
Author(s):  
Cyrille Hulin ◽  
Paul G. Richardson ◽  
Michel Attal ◽  
Hugh J. Goodman ◽  
Vadim A Doronin ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Median Time ◽  
Research Funding ◽  
Residual Disease ◽  
Response Rates ◽  
Complete Response ◽  
Advisory Committees ◽  
Depth Of Response ◽  
First Response

BACKGROUND: In multiple myeloma (MM), deep responses have been associated with improvements in progression-free survival (PFS) and overall survival (OS). Response kinetic data, including renal response times, which are highly important for patients with renal impairment, are infrequently reported. We analyzed the association between depth of response, including minimum residual disease (MRD) negativity, plus response kinetics and long-term outcomes, using data from the randomized, open-label, phase 3 ICARIA-MM study. ICARIA-MM evaluated the anti-CD38 monoclonal antibody isatuximab (Isa) in combination with pomalidomide and dexamethasone (Pd) versus Pd in patients with relapsed/refractory MM (RRMM) after ≥2 prior lines of therapy (NCT02990338). METHODS: All patients received standard doses of Pd and those randomized to the Isa-Pd group received 10 mg/kg IV on days 1, 8, 15, and 22 (cycle 1), and days 1 and 15 in subsequent 28-day cycles. Depth and kinetics of response were analyzed for each treatment group. MRD was assessed at 10-5 (tested by next-generation sequencing in patients with complete response [CR] / stringent CR [sCR]). Time to tumor response, time to renal response (CRenal; improvement in estimated glomerular filtration rate (eGFR), using the MDRD formula, from <50 mL/min/1.73m² at baseline to ≥60 mL/min/1.73m² at ≥1 post-baseline assessment), and time to sustained CRenal (a CRenal lasting ≥60 days) were recorded. No neutralization assay was used for patients with IgG kappa clonality. RESULTS: Overall, 307 patients were randomized to Isa-Pd (n=154) or Pd (n=153), of whom 33/142 (23.2%) and 24/145 (16.6%) patients had eGFR <50 mL/min/1.73m² at baseline. Patients had received a median of 3 prior lines of therapy (range 2-11) and 73.4% and 71.9% of patients in the Isa-Pd and Pd groups, respectively, were double refractory. Median PFS was 11.53 months with Isa-Pd and 6.47 months with Pd (hazard ratio [HR] 0.596; 95% confidence interval [CI] 0.436-0.814). Tumor responses on Isa-Pd were more frequent and deeper than on Pd. Overall response rates (ORR) were 60.4% vs 35.3% (odds ratio [OR] 2.80; 95% CI 1.72-4.56; p<0.0001); at least very good partial response rates (≥VGPR) were 31.8% vs 8.5% (OR 5.03; 95% CI 2.51-10.59; p<0.0001). As no isatuximab interference assay was performed, near-complete response rates (immunofixation remained positive) were reported: 15.6% vs 3.3% (OR 5.47; 95% CI 1.96-18.78; p=0.0002). MRD negativity rates in the ITT population were 5.2% vs 0%. Depth of response correlated with improved long-term outcomes in both arms (Figure). After a median follow-up of 11.6 months in the Isa-Pd arm, 100% of MRD-negative (MRD−) patients were progression free and alive. In the Isa-Pd arm, median PFS was longer with increased depth of response: MRD− patients, not reached (NR); ≥VGPR and MRD+, 15.21 months; partial response (PR), 11.53 months; less than PR, 3.29 months. This pattern was also observed for 1-year OS probabilities (100% > 92.9% > 82.4% > 46.4%, respectively). Tumor responses occurred faster with Isa-Pd than with Pd. Among patients who achieved a response of ≥PR (93 in the Isa-Pd arm and 54 in the Pd arm), the median time to first response was shorter for Isa-Pd (1.1 months) than for Pd (1.9 months). Among patients who achieved a response of ≥VGPR (49 and 13 in the Isa-Pd and Pd arms, respectively), the time to first VGPR or better response was similar at 2.9 months for Isa-Pd and 3.0 months for Pd. Renal responses occurred faster in patients on Isa-Pd than on Pd. A CRenal was observed in 23/32 (71.9%) patients in the Isa-Pd arm (median time to response 3.4 weeks) and in 8/21 (38.1%) of patients in the Pd arm (median time to response 7.3 weeks). A sustained CRenal was observed in 10/32 (31.3%) patients in the Isa-Pd arm (median time to first response 2.4 weeks) and in 4/21 (19.0%) patients in the Pd arm (median time to first response 4.8 weeks). CONCLUSION: In the heavily pretreated ICARIA population, Isa-Pd induced more frequent and faster tumor and renal responses than Pd. Depth of response, including MRD negativity, was improved with Isa-Pd and was clearly associated with better long-term survival outcomes. Figure. PFS (A) and OS (B) by best overall response and minimal residual disease for Isa-Pd Figure Disclosures Hulin: celgene: Consultancy, Honoraria; Janssen, AbbVie, Celgene, Amgen: Honoraria. Richardson:Sanofi: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Research Funding. Spicka:Novartis: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Sanofi: Consultancy; Amgen: Consultancy, Honoraria; Sanofi: Consultancy; Novartis: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Le-Guennec:Sanofi: Employment. Campana:Sanofi: Employment. van de Velde:Sanofi: Employment. Beksac:Celgene: Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. OffLabel Disclosure: Isatuximab is an investigational agent and has not been approved by the US Food and Drug Administration or any other regulatory agency worldwide for the uses under investigation.

scholarly journals Treatment Outcomes in Monoclonal Immunoglobulin Deposition Disease (MIDD): A Two Center Experience

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5591-5591
Author(s):  
Matthew J. Pianko ◽  
Timothy Tiutan ◽  
Jessica Flynn ◽  
Sean M Devlin ◽  
Insara Jaffer-Sathick ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Response Rate ◽  
Monoclonal Immunoglobulin ◽  
Advisory Committees ◽  
Renal Response ◽  
Treatment Regimens ◽  
Hematologic Response ◽  
Monoclonal Immunoglobulin Deposition Disease ◽  
Baseline Characteristics

Abstract Background: Monoclonal immunoglobulin deposition disease (MIDD) is a rare complication of plasma cell dyscrasias in which deposition of immunoglobulin light and/or heavy chains results in organ dysfunction, most commonly affecting the kidneys. MIDD can present with new onset hypertension, hematuria, renal insufficiency and proteinuria. The rarity of MIDD contributes to the uncertainty regarding optimal therapy (typically targeting the clonal plasma cells), and the relationship between hematologic response and renal outcome. We report here the experience at Memorial Sloan Kettering Cancer Center and New York Presbyterian Hospital/Weill Cornell Medical Center. Methods: An electronic query of pathology records was performed to identify patients with a biopsy-proven diagnosis of MIDD. Patients were eligible for inclusion in this analysis if they had received treatment and had been subsequently followed at either institution. A retrospective review of clinical records extracted patients' baseline characteristics and treatment history. Hematologic responses were assessed according to International Myeloma Working Group uniform response criteria (Kumar, S. et al 2016 Lancet Oncol 17(8): e328-346) and renal organ responses were evaluated based on changes in serum creatinine (SCr), and proteinuria, a modification of criteria previously reported (Kourelis, T. V., et al 2016, Am J Hematol 91(11): 1123-1128.; Nasr, S.H. et al. 2009, J Am Soc Nephrol 20(9): 2055-2064. The primary objective was to determine the rate of hematologic response after initial therapy. Secondary objectives included: (i) Estimation of renal response rate; (ii) Identification of risk factors associated with renal response using the Wilcoxon Rank Sum and Fisher's Exact Tests. Results: Among 54 patients identified who were diagnosed and started treatment between 1/1999 and 1/2016, 29 met criteria for inclusion. Baseline characteristics at diagnosis included: Median age of 50 (range, 32-79); 17 (59%) were male; 22 (75%) had hypertension. Renal parameters at diagnosis: median SCr of 2.4 mg/dl (range, 0.4-19), median CrCl 23 ml/min (range, 4-131), median proteinuria 2383.7mg/24h (range 4.7-13,000), nephrotic-range proteinuria syndrome in 13 (45%), hematuria in 4/25 pts (16%; 4 unknown), 7 were on hemodialysis (HD) prior to initiation of therapy, and 26 (90%) patients had monoclonal kappa light chain deposits. Hematologic parameters included median free light chain ratio of 67.9 (2.8-1179.0), detectable M-spike in 11 pts with a mean level of 0.6 g/dL and median bone marrow plasmacytosis of 20% (range, 0-90%). Induction treatment regimens included bortezomib in 18 (62%), lenalidomide in 6 (21%), cyclophosphamide in 8 (28%), and 21 (73%) underwent autologous stem cell transplant (ASCT) during the course of their treatment. Outcomes are shown in Table 1. Hematologic response among the 29 pts at completion of first line therapy included an overall response rate (ORR) of 93% with sCR (N=14, 48%); CR (N=5, 17%), VGPR (N=6, 20%), PR (N=2, 6.9%), Not available (N=2, 7%). Renal response (Table 1) among 29 patients included CR (N=9, 31%), PR (N=14, 48%) and End Stage Renal Disease (ESRD) (N=6, 21%). Among 7 patients on HD at baseline, 3 remained on HD despite treatment, while 4 stopped HD after treatment, 2 as a result of the treatment and 2 after renal transplant. 3 patients progressed to ESRD and required HD during treatment. Baseline beta-2 microglobulin (B2M), SCr, and eGFR at diagnosis were factors associated with renal response (p<0.05). Hematologic response (CR vs. non-CR) was not associated with renal response (p=0.68) in this cohort. Conclusions: In this cohort, we observed a high rate of hematologic response (65.5% reaching CR) to upfront treatment regimens. A majority of patients received bortezomib-based regimens and ASCT. We observed a large proportion of patients whose renal impairment from MIDD improved significantly after receiving therapy directed at the underlying clonal neoplasm, with 75.8% reaching PR or better, nearly a third of patients achieving a renal CR, and 2/7 patients on HD at diagnosis discontinuing HD after treatment. Our experience presented here serves to inform the treatment approach of patients with MIDD. Given the scarcity of outcome data in MIDD, especially in the era of novel anti-myeloma therapy, prospective studies to optimize the management of these patients are needed. Disclosures Rossi: Celgene: Consultancy. Smith:Celgene: Consultancy, Patents & Royalties: CAR T cell therapies for MM, Research Funding. Korde:Amgen: Research Funding. Mailankody:Janssen: Research Funding; Juno: Research Funding; Physician Education Resource: Honoraria; Takeda: Research Funding. Lesokhin:Squibb: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Genentech: Research Funding; Janssen: Research Funding; Serametrix, inc.: Patents & Royalties: Royalties. Landgren:Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Consultancy; Merck: Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy; Celgene: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Hassoun:Oncopeptides AB: Research Funding.

scholarly journals Ibrutinib and Obinutuzumab in CLL: Improved MRD Response Rates with Substantially Enhanced MRD Depletion for Patients with >1 Year Prior Ibrutinib Exposure

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 181-181 ◽  
Author(s):  
Andy Rawstron ◽  
Talha Munir ◽  
Kristian Brock ◽  
Nichola Webster ◽  
Samuel Munoz Vicente ◽  
...  
Keyword(s):  
Adverse Events ◽  
Board Of Directors ◽  
Research Funding ◽  
Response Rate ◽  
Response Rates ◽  
Extension Study ◽  
Advisory Committees ◽  
Equity Ownership ◽  
Anti Cd20 ◽  
Support Research

Abstract Background: Ibrutinib inhibits CLL cell proliferation and results in prolonged remission, but MRD responses are rare. Obinutuzumab is a second generation anti-CD20 monoclonal antibody that is effective in CLL and can result in MRD responses. In the IcICLLe study (ISRCTN12695354), 40 participants with CLL requiring treatment (20 treatment-naïve, 20 with relapsed/refractory [R/R] disease) received ibrutinib until complete remission with <0.01% Minimal Residual Disease (MRD) in the bone marrow or disease progression. The IcICLLe Extension Study expanded IcICLLe to examine the efficacy and safety of the combination of obinutuzumab and ibrutinib in 40 patients with R/R CLL, of which 10/40 had received prior ibrutinib on the IcICLLe trial. Initial results after 1 month of combination treatment indicated that adding obinutuzumab to ibrutinib improved CLL depletion, and 18 month follow-up data is now available. Aim: to determine the MRD response rates for patients with R/R CLL treated with ibrutinib and obinutuzumab in ibrutinib-naïve trial participants compared to those treated with >1 year prior ibrutinib. Patients: The IcICLLe Extension Study recruited 40 participants with relapsed/refractory CLL requiring treatment. They received continuous ibrutinib (420mg OD) with 6 cycles of obinutuzumab given over 6 months (M). Ten participants had >1 year of prior ibrutinib monotherapy in IcICLLe and 30 were ibrutinib-naïve with obinutuzumab started 24 hours after first ibrutinib dose. Patient characteristics and Adverse Events (AEs, collected from registration until 30 days after treatment cessation and reported at 1, 3, and 6M, and 6-monthly thereafter using the Common Terminology Criteria for Adverse Events v4.0) are shown in Table 1. MRD assessment was performed according to ERIC guidelines with a maximum detection limit of 0.001%/10-5. Results: In the 20 R/R patients treated with ibrutinib monotherapy there were no IWCLL CR/CRi responses and no patients achieved <0.01% CLL in the PB or BM at the 6 month response assessment. PB MRD levels either remained stable or improved at subsequent timepoints, with 1/20 achieving <0.01% PB MRD at 18M. The addition of obinutuzumab did not have a discernible impact on safety but was associated with a higher response rates and greater depth of MRD depletion than observed in patients treated with ibrutinib monotherapy, particularly in patients who had received ibrutinib for >1 year prior to combination with obinutuzumab (see Table 1). Patients receiving obinutuzumab after >1 year prior ibrutinib monotherapy achieved a higher response rate compared to ibrutinib-naive patients (IWCLL CR/CRi 50% vs. 30%), with a higher proportion of patients achieving <0.01% BM MRD (50% vs. 6%) and a greater depth of disease depletion (3.1 vs. 1.5 log reduction). PB MRD levels continued to improve in ibrutinib-naïve patients after cessation of obinutuzumab with 30% (9/30 with 4/30 inevaluable) achieving PB MRD <0.01% rate at 12 months post-obinutuzumab, compared to 60% (6/10 with 2/10 inevaluable) of patients at the same timepoint (12 months post-obinutuzumab) who had received ibrutinib for >1 year prior to starting obinutuzumab. The difference in extent of disease depletion observed with obinutuzumab may be related to the pre-obinutuzumab disease bulk because the majority of patients (7/10) with >1 year prior ibrutinib treatment had already resolved any lymphadenopathy prior to receiving obinutuzumab. Conclusions: The results suggest that the addition of obinutuzumab to ibrutinib may result in a substantial improvement in the depletion of CLL cells from the PB and BM for ibrutinib-naïve patients. However, a greater impact in MRD response rate and depth of depletion was seen when obinutuzumab was introduced after >1 year of ibrutinib treatment and tumour bulk was low. For patients with persistent disease during/ following pathway inhibition treatments, the addition of anti-CD20 antibody therapy may be effective at improving MRD response rates. Disclosures Rawstron: Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; BD Bio-sciences: Research Funding; Beckman Coulter: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Consultancy, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding. Munir:MorphoSys: Membership on an entity's Board of Directors or advisory committees; Alexion: Honoraria; Novartis: Honoraria; Gilead: Honoraria; Janssen: Honoraria; Abbvie: Honoraria. Brock:GlaxoSmithKline: Equity Ownership; AstraZeneca: Equity Ownership; Merck Sharp Dohme: Other: Reimbursement of conference fees; Roche: Other: Reimbursement of expenses; Lilly: Honoraria. Pettitt:AstraZeneca: Research Funding; Celgene: Research Funding; Chugai: Research Funding; Roche: Research Funding; GSK/Novartis: Research Funding; Gilead: Research Funding; Napp: Research Funding. Fox:Celgene: Consultancy, Other: Travel support, Speakers Bureau; Janssen: Consultancy, Other: Personal fees and non-financial support, Speakers Bureau; Gilead: Consultancy, Other: Travel support, Research Funding, Speakers Bureau; AbbVie: Consultancy, Other: Travel support, Research Funding, Speakers Bureau; Roche: Consultancy, Other: Travel support, Research Funding, Speakers Bureau; Sunesis: Consultancy. Devereux:Janssen: Other: Personal fees; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Fegan:Janssen: Honoraria; Gilead Sciences, Inc.: Honoraria; Abbvie: Honoraria; Roche: Honoraria; Napp: Honoraria. Bloor:Janssen: Research Funding; AbbVie: Research Funding. Hillmen:Alexion Pharmaceuticals, Inc: Consultancy, Honoraria; Acerta: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Novartis: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding; Gilead Sciences, Inc.: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

scholarly journals A Phase II, Open-Label, Single Arm Trial to Assess the Efficacy and Safety of the Combination of Tisagenlecleucel and Ibrutinib in Mantle Cell Lymphoma (TARMAC)

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 34-35
Author(s):  
Adrian Minson ◽  
Nada Hamad ◽  
Jason P Butler ◽  
David Alan Westerman ◽  
David Ritchie ◽  
...  
Keyword(s):  
T Cell ◽  
Mantle Cell Lymphoma ◽  
Board Of Directors ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Response Rates ◽  
Complete Response ◽  
Advisory Committees ◽  
Car T ◽  
Mantle Cell

Background Mantle cell lymphoma (MCL) is a clinically and pathogenetically distinct B-cell non-Hodgkin lymphoma that presents at a median age of 65 years and typically at an advanced stage. High dose chemotherapy and stem cell transplantation can achieve durable responses, but disease eventually relapses in most patients. Allogeneic transplantation can achieve a cure in some but is only suitable for a minority of younger, fitter patients who achieve remission to salvage but carries risks of GVHD. Bruton tyrosine kinase inhibitors (BTKi) are active in relapsed MCL but the median PFS is generally less than 2 years and ibrutinib failure is associated with particularly poor outcomes (Cheah et al., Ann Oncol 2015). Mutations of TP53 are associated with refractoriness to both chemotherapy and novel agents (Eskelund et al., Blood 2017), and patients with disease harboring these mutations are in particular need of more effective therapies. Promising activity has recently been demonstrated with chimeric antigen receptor T-cells (CAR T), albeit with significant rates of cytokine release syndrome (CRS) and neurotoxicity (Wang et al., New England Journal of Medicine 2020), resulting in FDA approval of brexucabtagene autoleucel in MCL. Rationale Tisagenlecleucel (Novartis) is a CAR T-cell product directed against CD19 that is approved in many countries for the treatment of relapsed DLBCL and ALL. MCL consistently expresses CD19 at diagnosis and relapse and is therefore a promising target. Pre-clinical data suggests synergistic effects if tisagenlecleucel is combined with the BTKi ibrutinib. The proposed mechanism includes enhancing T cell activation and expansion (Fraietta et al., Blood 2016), disrupting the MCL nodal environment (Long et al., The Journal of Clinical Investigation 2017) and mitigating CRS (Ruella et al., Clin Cancer Res 2016). Clinical trials in CLL show that the combination is safe and effective, including deep minimal residual disease negative responses (Gill et al., Blood 2018, Gauthier et al., Hematological Oncology 2019). We hypothesise that combination treatment will be tolerable and improve outcomes in a poor risk MCL population. Combination, time-limited therapy would also avoid the burdens of continuous treatment. Study Design and Methods 20 adult patients with MCL that has relapsed following front-line therapy, or those patients with MCL with TP53 aberrations who have achieved less than complete response on PET imaging after 2 cycles of induction will be enrolled (See Fig 1. for inclusion and exclusion criteria). Treatment consists of 560mg oral ibrutinib followed by a single infusion of tisagenlecleucel. Autologous lymphocytes for CAR T manufacture will be collected after a minimum of 7 days of continuous ibrutinib therapy. Ibrutinib will be continued during CAR T manufacture and for 6 months after infusion (see Fig 2.) Patient characteristics will be presented using descriptive statistics, response rates will be calculated as percentages using exact methods from the binomial distribution, and progression-free survival, duration of response and overall survival will be described using the Kaplan-Meier method. The primary objective is to estimate the complete response (CR) rate at month 4 following tisagenlecleucel infusion in combination with ibrutinib with the primary endpoint being CR rates at month 4 post tisagenlecleucel using the Lugano criteria. Secondary objectives include estimating MRD negative response rates, response rates according to TP53 status, and safety of the combination. Exploratory translational studies include studies of T cell repertoire and phenotype during ibrutinib exposure and after tisagenlecleucel infusion. The role of circulating tumour DNA monitoring in the management of MCL is also being evaluated. The trial is investigator led, sponsored by the Peter MacCallum Cancer Centre, with additional sites throughout Australia. The study was initiated in April 2020 and is actively recruiting patients. The trial is registered at ClinicalTrials.gov: NCT04234061. Disclosures Hamad: Abbvie: Honoraria; Novartis: Honoraria. Blombery:Janssen: Honoraria; Amgen: Consultancy; Invivoscribe: Honoraria; Novartis: Consultancy. Seymour:Nurix: Honoraria; Morphosys: Consultancy, Honoraria; Mei Pharma: Consultancy, Honoraria; Gilead: Consultancy; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Tam:Pharmacyclics LLC, an AbbVie Company: Honoraria; BeiGene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding. Dickinson:Janssen: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; Merck Sharp & Dohme: Consultancy. OffLabel Disclosure: Tisagenlecleucel is not currently approved for use in MCL.

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